Interstitial fluid collection and constituent measurement

ABSTRACT

An apparatus and method is disclosed for obtaining and measuring constituents in a sample of body fluid. The apparatus includes a member which is sized to penetrate into at least the dermal layer of skin to collect a sample of body fluid located within the dermal layer.

I. CROSS-REFERENCE RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/604,018, filed Jun. 26, 2000 now U.S Pat. No. 6,602,205, which is acontinuation of U.S. patent application Ser. No. 09/169,155, filed Oct.9, 1998 now U.S. Pat. No. 6,080,116, which is a continuation of Ser. No.08/919,033, filed Aug. 27, 1997 now U.S. Pat. No. 5,820,570, which is acontinuation of Ser. No. 08/555,314, filed Nov. 8, 1995 now U.S. Pat.No. 5,746,217, which is a divisional of Ser. No. 08/321,305, filed Oct.11, 1994 now U.S. Pat. No. 5,582,184, which is a continuation-in-part ofSer. No. 08/136,304, filed Oct. 13, 1993 now abandoned.

II. BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an apparatus for testing body fluidconstituents. More particularly, the present invention pertains to anapparatus for collecting body fluid for testing.

2. Description of the Art

The prior art has long been seeking procedures for testing anddetermining the level of blood constituents. Particularly, a great dealof attention has been spent on the development of techniques formeasuring blood glucose.

Historically, blood glucose and other bodily analyte measurements were,and remain, invasive. Such measurements are generally made bywithdrawing a blood sample and measuring the desired analyte within theblood or plasma. Blood samples can be withdrawn by inserting a needleinto a major artery or, more commonly, a vein. A syringe or other deviceis used to provide any necessary suction and collect the blood sample.Needles used for this sampling technique must be long enough to passthrough the skin, subcutaneous tissue, and blood vessel wall. The needlemust also have a sufficient diameter to allow timely collection of theblood sample without causing hemolysis of the blood. Minimal diameter tomeet these criteria is generally 20 gauge or larger diameter. Suchdirect vascular blood sampling has several limitations, including pain,hematoma and other bleeding complications, and infection. In addition,due to the vascular damage resulting from the needle puncture, samplingcould not be repeated on a routine basis. Finally, it is extremelydifficult for patients to perform a direct vascular puncture onthemselves.

The other common technique for collecting a blood sample is to cut orlance the skin and the subcutaneous tissue, including the small,underlying blood vessels, to produce a localized bleeding on the bodysurface. A lancet, knife, or other cutting device is required. The bloodon the body surface can then be collected into a small tube or othercontainer. The fingertip is the most frequently used site to collectblood in this method due to the large number of small blood vesselslocated in the region. One method is shown in U.S. Pat. No. 4,637,403.This sampling method also suffers from several major disadvantages,including pain and the potential for infection and other problemsassociated with repeated sampling for a confined area. Pain is a majordisadvantage since the fingertip has a large concentration of nerveendings. Also, there is a limited body surface area from which to takethese samples and measurement on a high frequency basis.

Because the prior art invasive techniques are painful, patientsfrequently avoid having blood glucose measured. For diabetics, thefailure to measure blood glucose on a prescribed basis can be verydangerous. Also, the invasive techniques, which would result in lancingblood vessels, create an enhanced risk for disease transmission.

Attempts have been made to develop glucose and other analyte sensors forimplantation in the human body. Implanted glucose sensors would beprimarily to control insulin infusion pumps or provide continuous,chronic monitoring. Development of a permanently implanted or long-term,chronic implanted sensor has been unsuccessful. Attempts to developshort-term implantable sensors (up to 2–3 days) have also met with verylimited success. Most implantable sensors are based on measuring variousproducts from chemical reactions between agent(s) located on or withinthe sensor and the desired analyte. Implanted glucose sensors havetypically used the glucose oxidase reaction to measure the amount ofglucose, as described in U.S. Pat. No. 5,108,819. Such implantableglucose sensors have been intended for insertion through the epidermisand dermis to the subcutaneous tissue. An alternative locationpreviously described for chronic sensor implant is the peritonealcavity. All such implanted sensors require direct or telemeteredconnection to a measurement instrument, usually located external thebody.

All implanted sensors are faced with several major problems. First, allforeign materials, including materials incorporated into a glucosesensor, produce unwanted body reactions. Such reactions include theformation of fibrotic tissue around the sensor which alters the sensor'scontact with normal body fluids and analytes, such as glucose. Thebody's natural defense mechanism may also have a direct “poisoning”effect upon the sensor's operation by interfering with the chemicalreactions required by chemical-based sensors. As with any implantedobject, implanted sensors may also initiate other bodily reactionsincluding inflammation, pain, tissue necrosis, infection, and otherunwanted reactions.

Implanted sensors require certain chemicals and chemical reactions todetermine the level of analyte in the surrounding medium. These chemicalreactions are the source of the other major problem facing anyimplantable sensor. Chemically-based sensors require products to beconsumed and other products to be produced as part of the sensor'snormal operations. Therefore, the sensors can quickly be depleted of thechemical agents required to sustain the desired chemical reactions.Secondly, by-products are given off as a result of the basic chemicalreaction. These by-products often “poison” the sensor or cause otherunwanted tissue reactivity. Because of these severe limitations,implanted sensors are not practical. Finally, such implanted sensors arepainful to implant and are a source of infection.

By withdrawing the body fluid containing the glucose or other analyteand making the measurement outside the body, these aforementioned sensorbased problems can be avoided. Specifically, there is no concern aboutthe chronic tissue response to the foreign sensor material or thelimited operational life of the sensor due to the consumption ofreaction agents or the production of unwanted by-products from thatreaction.

In view of the risk associated with invasive techniques, the prior arthas sought to develop non-invasive blood glucose measurement techniques.An example of such is shown in U.S. Pat. No. 4,882,492 to Schlager.Schlager teaches a non-invasive near-infrared measurement of blood.Schlager is particularly directed to the measurement of blood glucoselevels. The Schlager patent recognizes that certain wavelengths of lightin the near-infrared spectrum are absorbed by glucose. Modulated lightis directed against a tissue (shown as an earlobe). The light is eitherpassed through the tissue or impinged on a skin surface. The light isspectrally modified in response to the amount of analyte (for example,glucose) in the blood and tissue. The spectrally modified light is splitwith one beam passed through a correlation cell. The other beam ispassed through a reference cell. The intensity of the beams passingthrough the correlation cell and the reference cell are compared tocalculate a glucose concentration in the sample. Other non-invasiveblood glucose methods are shown in U.S. Pat. Nos. 4,805,623, 4,655,225,4,014,321 and 3,958,560.

One drawback of prior art non-invasive systems is that by passing theinfrared light through a complex medium (such as an earlobe) verycomplex data is generated. Algorithms must be developed to manipulatethe data in order to attempt to provide reliable indications of bloodglucose measurements. Also, such devices may require exact placement ofthe measuring device (e.g., precise placement on a patient's finger ornear an earlobe) to minimize measurement error. Such devices may also bedifficult to calibrate. To date, the prior art has not developedcommercially available non-invasive methods which provide accurate data.

In addition to the foregoing, applicants' assignee is the owner ofvarious patents pertaining to blood glucose measurement. For example,U.S. Pat. No. 5,179,951 to Knudson dated Jan. 19, 1993 teaches aninvasive blood glucose measurement where infrared light is passedthrough a sample of blood by use of an implanted catheter. Similarly,U.S. Pat. No. 5,079,421 teaches such a system.

U.S. Pat. No. 5,146,091 teaches a non-invasive blood glucose measurementutilizing FTIR (Fourier Transform Infrared) techniques to determineblood glucose levels and U.S. Pat. No. 5,115,133 which directs infraredlight to the eardrum. As indicated in the aforementioned commonlyassigned patents, the testing wavelength includes a glucose sensitivewavelength of about 500 to about 4,000 wave numbers (cm⁻¹). Preferably,the glucose absorbable wavelength is about 1,040 wave numbers.

It is an object of the present invention to provide an enhancedtechnique for collecting a sample fluid and for measuring fluidconstituents in the sample.

III. SUMMARY OF THE INVENTION

According to a preferred embodiment of the present invention, anapparatus and method are disclosed for collecting and measuringconstituents in a sample of body fluid. The method includes urging asampler against a subject's skin. The sampler includes a penetrationmember which is sized to penetrate the subject's skin upon the urging ofthe sampler. A sample of fluid is drawn along the penetration member.The sample is tested for desired constituents such as glucoseconcentration.

In one embodiment, a body fluid is drawn from the dermal layer of skin.The apparatus includes a conduit which is sized to penetrate into thedermal layer. Light having a wavelength absorbable by the constituent ispassed through the conduit. The amount of absorption indicates theamount of constituent in the drawn sample. Alternative embodiments ofthe present invention include drawing a sample of fluid and depositingthe sample on, within or between a membrane(s) or substrate(s). Thesample deposited on, within or between the membrane(s) or substrate(s)is tested for constituents.

The present invention provides numerous advantages over the prior arttechniques. Compared to the prior art invasive and non-invasivetechniques, the present invention may more accurately be referred to asa minimally invasive technique.

The present invention utilizes a small needle for drawing a minuteamount of fluid. Preferably, the fluid is drawn from the dermal layer ofthe skin. The dermal layer of the skin has smaller nerves compared tothe subcutaneous layer of the skin. Accordingly, the pain associatedwith prior art invasive techniques is substantially avoided resulting inincreased probability of a patient's compliance with prescribed testing.Also, the total body area from which a sample may be taken is notrestricted to a fingertip. Furthermore, smaller blood vessels outside ofthe subcutaneous layer result in minimal or no blood loss and bloodvessel rupture by reason of the testing. These and other advantages ofthe present invention will become apparent through the followingdetailed description of the invention.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front sectional view of an apparatus according to thepresent invention shown inserted into a layer of skin;

FIG. 2 is a detailed sectional view of a portion of a preferredembodiment of the present invention shown inserted in a layer of skin;

FIG. 3 is a detailed sectional view of the apparatus shown in FIG. 2;

FIG. 4 is a side elevation view of a portion of the apparatus of FIG. 3shown in an analysis apparatus (shown schematically);

FIG. 5 is a front elevation view of the apparatus of FIG. 4;

FIG. 5A is a top plan view of a detection apparatus;

FIG. 6 is an enlarged side sectional view of the apparatus of FIG. 2;

FIG. 7 is a detailed sectional view of an alternative embodiment of thepresent invention shown inserted in a layer of skin;

FIG. 8 is a front sectional view of the apparatus shown in FIG. 7 withlight transmitting and detecting devices secured to the apparatus;

FIG. 9 is a prospective view of the apparatus shown in FIG. 7;

FIG. 10 is a further alternative embodiment of the apparatus of FIG. 7;

FIG. 11 is a perspective view of a sampler according to an alternativeembodiment of the present invention with a cover shown in the openposition;

FIG. 12 is a top plan view of the sampler of FIG. 11;

FIG. 13 is a bottom plan view of the sampler of FIG. 11;

FIG. 14 is a rear elevation view of the sampler of FIG. 11;

FIG. 15 is a side elevation of the sampler of FIG. 11;

FIG. 16 is a perspective view of a still further alternative embodimentof a sampler according to the present invention;

FIG. 17 is a top plan view of the sampler of FIG. 16;

FIG. 18 is a bottom plan view of the sampler of FIG. 16;

FIG. 19 is a side elevation view of the sampler of FIG. 16;

FIG. 20 is a view taken along lines 20—20 of FIG. 19;

FIG. 21 is side elevation view of a needle for use in the sampler ofFIG. 16;

FIG. 22 is the view of FIG. 21 rotated 90°;

FIG. 23 is an exploded perspective view of the sampler of FIG. 16;

FIG. 24 is a side elevation view of a yet further embodiment of thepresent invention;

FIG. 25 is a top plan view of the sampler of FIG. 24; and

FIGS. 26–31 illustrate a split sleeve penetration member.

V. DESCRIPTION OF PREFERRED EMBODIMENTS

A. Fluid Sampling Generally

Referring now to FIG. 1, an apparatus 10 is shown for use inminimally-invasive testing for a body fluid constituent. While theillustrated application is a preferred embodiment, it will beappreciated that the salient features are applicable to a wide varietyof body constituents found in body fluid.

In FIG. 1, the apparatus 10 according to the present invention is shownin its most elementary structure for ease of illustration. The apparatus10 is for collecting a sample of fluid.

The apparatus 10 includes a penetration member in the form of a conduit12, preferably a hollow capillary type tube, which is open at both endsand which is inserted into a layer of skin 20. As shown in FIG. 1, thestructure of the skin 20 includes three distinct layers, the epidermis22, which is the top thin layer, the dermis 24, or middle layer, and thesubcutaneous layer 28. Commonly, the epidermis is about 100 micronsthick, the dermis 24 is about 2,000–3,000 microns thick.

The collection apparatus 10 is designed and dimensioned for insertioninto the dermal layer 24 of the skin without penetration into thesubcutaneous layer 28. The dermal layer 24 generally consists of a densebed of connective tissue including collagen fibers. It is currentlybelieved bodily fluid is present in the interstitial space definedbetween the collagen fibers and cells. This interstitial, dispersedbodily fluid includes constituents, such as glucose, in a concentrationrepresentative of the constituent's concentration in other bodilyfluids, such as blood. Thus, this interstitial fluid may be tested toaccurately measure the level of constituents present in an individual'sbodily fluids (e.g., blood sugar levels). While it is believed low blood(i.e., few or no red cells) interstitial fluid is preferred any bodyfluid may be collected through the present invention. However, for easeof illustration, the body fluid will be referred to herein asinterstitial fluid.

According to the present invention, the capillary tube 12 is insertedinto the dermal layer 24 of the skin to collect a sample of interstitialfluid for subsequent testing of a level of a constituent in theinterstitial fluid. In order to collect interstitial fluid with minimalpain, a capillary tube 12 with inside diameter of 114 microns andoutside diameter of 140 microns is presently preferred. In the preferredembodiment, the interstitial fluid is to be tested to measure the levelof glucose in the fluid.

The capillary tube 12 is inserted to a position in which the distal end14 of the tube 12 is approximately in the upper third portion 24 a ofthe dermal layer 24 to ensure the subcutaneous layer 28 is notpenetrated. The capillary tube 12 is disposed in this position whileinterstitial fluid located adjacent to the distal end 14 of the tube 12is drawn up inside the tube 12 and retained within the internalpassageway 18 of the tube 12.

B. IR Testing Generally

Discussed more fully with respect to the embodiments of FIGS. 11–22, thecollected sample of interstitial fluid may be deposited on a membranefor subsequent IR testing or may be tested through other means(including electrochemical or colormetric). The following discussiondiscusses IR testing through the tube 12 as one means of constituenttesting.

For IR testing of a sample in tube 12, the capillary tube 12 includes atleast a section of the tube 12 which is selected to pass certainpredetermined light wavelengths (e.g.—wavelengths which are absorbableby constituents which are to be measured). This allows forspectrophotometric analysis of the constituents in the interstitialfluid without the need for pipetting or transferring the fluid in anymanner. For purposes of this application and any appended claims, theterm “light” is intended to mean both the visible and invisible (e.g.,infrared) spectra.

Once the interstitial fluid is retained in the capillary tube 12, atesting light which includes wavelengths absorbable by the constituentto be tested, is generated and directed through the capillary tube 12containing the constituent of the interstitial fluid. By measuring theamount of absorption of the absorbable wave length, the level of theconstituent in the interstitial fluid may be calculated.

In one embodiment, the entire tube 12 is made of a material to pass atest wavelength. When testing for glucose with infrared energy at 1040wavenumbers, a preferred material is nylon, polyethylene or polyamide,which is at least partially transparent to infrared light wavelengths.However, while the specifically mentioned materials are currentlypreferred, it will be appreciated other materials may suffice. Infraredlight having a wavelength absorbable by blood glucose then is directedthrough the capillary tube to measure the level of glucose in theinterstitial fluid.

C. Detailed Discussion of Embodiment for Testing Sample in Tube

Referring to FIGS. 2 and 3, a preferred embodiment of an apparatus 10′for collecting interstitial fluid is shown. It is appreciated that whilethis embodiment illustrates a structure for inserting the capillary tube12 to a predetermined depth within the dermal layer 24 of the skin 20and drawing interstitial fluid into the capillary tube 12, numerousother devices could be effectively utilized in accordance with theprincipals of the present invention to accomplish the same results.

As shown in FIGS. 2 and 3, the collection apparatus 10′ includes acapillary tube 12 and a hollow needle 42. The capillary tube 12 issecurely retained within the needle 42 so that the distal end 14 of thecapillary tube 12 is disposed adjacent the insertion tip 44 of theneedle 42. Preferably the tip 44 of the needle 42 is designed tofacilitate quick and efficient penetration of the skin. In the preferredembodiment, the needle 42 is selected with a small diameter (30 gauge)to minimize or eliminate the pain of insertion.

The needle 42 includes opposing axially extending slots 46 which exposea portion of the capillary tube 12 such that a testing light may bedirected through slots 46 and through capillary tube 12 while thecapillary tube 12 is retained within the needle 42. It is noted thatwhile the preferred embodiment provides for testing of the constituentin the interstitial fluid with the capillary tube 12 retained in theneedle 42, alternatively, the capillary tube 12 could be removed fromthe needle 42 after collection of the interstitial fluid for testing ofthe interstitial fluid constituents.

The collection apparatus 10′ includes a spacer member 60 which isdesigned to control the depth of the penetration of the needle 42. Thespacer member 60 has a generally cylindrical shape and encircles theneedle 42. A proximal end 45 of the needle 42 is secured to a mountingplate 48 having an opening 52 (shown in FIG. 2 only) corresponding tothe outer diameter of the needle 42 such that the needle is securelyattached to the mounting plate 48. The mounting plate 48 is sized to fitwithin the spacer member 60. Preferably, the spacer member 60 includesmounting clips or other appropriate structure (e.g. an annular groovesized to receive a peripheral edge of plate 48) positioned on the innerwall 64 of the spacer member 60 to securely attach the mounting plate 48to the spacer member 60. The tip 44 of the needle assembly and thedistal end 14 of the capillary tube extend a predetermined distancebeyond the bottom 61 of the spacer member 60.

In operation, the spacer member 60 is placed against the surface of theskin 20 such that the needle 42 penetrates into the skin. As shown inFIG. 2, with the spacer member 60 placed firmly against the skinsurface, the tip 44 of the needle 42 extends into an upper portion 24 aof the dermal layer 24 of skin. In the preferred embodiment, the tip 44of the needle 42 is inserted such that the effective depth of the distalend 14 of the capillary tube 12 is about 0.7 mm. Generally, the dermallayer of the skin is 2–3 mm deep and thus the insertion of the capillarytube to a depth of 0.7 mm places the capillary in the upper thirdportion 24 a of the dermal layer 24 and away from the subcutaneous layer28. In this way, the capillary tube 12 is positioned to obtain a cleansample of interstitial fluid. If the capillary tube 12 were to beinserted further into the dermal layer 24, the potential for thecapillary tube entering the subcutaneous level of the skin increases.The subcutaneous layer 28 of the skin includes fatty tissue cells,relatively large blood vessels and large nerves and, as currentlybelieved by applicants, does not provide for a low blood sample ofinterstitial fluid. Thus, the present invention preferably positions thecapillary tube 12 in the upper third portion 24 a of the dermis 24without extending through the dermis 24 into the subcutaneous layer 28to minimize the pain of the insertion and while also obtaining a lowblood sample of interstitial fluid.

In accordance with the present invention, once the capillary tube 12 isinserted into the dermal layer 24, interstitial fluid located adjacentto the distal end 14 of the capillary tube 12 is urged up into thecapillary tube 12 and retained therein. This may be achieved throughvarious methods. For example, capillary action, negative pressure, orcompressing the skin 20 surrounding the apparatus 10 may all be utilizedto urge interstitial fluid into the passageway 18 of the capillary tube12.

A vacuum generating mechanism 70 may be provided to assist the flow ofinterstitial fluid into the capillary tube 12. Shown best in FIG. 2, thevacuum mechanism 70 includes an outer cylindrical wall 72 and a housing74 defining an inner chamber 76. The outer wall 72 is secured to themounting plate 48 of the needle 42 with the vacuum housing 74 movablydisposed against the outer wall 72. The proximal end 17 of the capillarytube 12 and proximal end 45 of needle 42 extend into the inner chamber76 of the housing 74. A seal 80 is provided between the needle 42 andthe tube 12.

The vacuum mechanism 70 includes a plunger 82 which is secured to thehousing 74 to move the housing between an upper and lower position. Whenthe collection apparatus 10′ is first placed against the skin so that aportion of the needle assembly 40 is inserted into the dermal layer ofthe skin, the housing 74 is in a lower position. The plunger 82 is thenpulled upward with the housing 74 correspondingly moving upward againstthe outer wall 72 of the vacuum mechanism 70. As the housing 74 israised upward, the volume of the inner chamber 76 increases whichdecreases the pressure adjacent to the proximal end 17 of the capillarytube 12. This results in a negative pressure which provides anadditional force to urge interstitial fluid into the passageway 18 ofthe capillary tube 12.

The spacer member 60 is also designed to improve the flow ofinterstitial fluid into the capillary tube 12 in addition to controllingthe depth of penetration of the needle assembly 40. As shown in FIGS. 2and 6, the bottom edge 61 of the spacer member 60 compresses the skin 20around the needle 42. This compression improves the flow of theinterstitial fluid located in the dermal layer 24 into the capillarytube 12. Once a sample of interstitial fluid is drawn into and retainedin the passageway 18 of the capillary tube 12, the constituents in theinterstitial fluid may now be measured to determine the concentration ofthe constituent. Any pressure or vacuum is applied only to collectfluid. Such pressure or vacuum is not used to retain the fluid in tube12 and is optional to enhance collection.

In accordance with the present invention, various methods ofspectrophotometric analysis may be performed on constituents in theinterstitial fluid once a sample has been retained in the capillary tube12. These measurement techniques utilize a testing light of knownintensity including a wavelength absorbable by the constituent beingmeasured which is then directed toward the constituent of theinterstitial fluid. Also, a reference wavelength is preferably utilized.A light detector is provided for measuring the intensity of the testinglight being spectrally modified by the constituent. Based on absorptionanalysis, the concentration of the constituent can then be calculated.It will be appreciated that while several methods for calculating theconcentration of the constituent are disclosed herein, various othermethods may be utilized which incorporate light analysis to calculatethe concentration of the constituent in the interstitial fluid.

FIGS. 4, 5 and 5A schematically illustrate the testing for blood glucoseutilizing the present invention. After collection of interstitial fluidinto the capillary tube through the above-mentioned apparatus andmethod, the spacer member 60 is removed. An infrared radiation source 92(shown as a heating coil) is provided opposing the needle 42 andcapillary tube 12. As indicated, the needle 42 has openings or slots 46to permit infrared radiation to pass directly to and through thecapillary tube 12.

Filters 94, 95 are contained on a wheel 96 placed between the infraredsource 92 and the tube 12. The filters 94, 95 filter out energy atundesirable wavelengths such that only energy at wavelengths thatcontain useful information is allowed to enter the tube 12. For example,filter 94 passes a glucose absorbable test wavelength (e.g., 1040wavenumber) and filter 95 passes a reference wavelength (e.g., 960wavenumber). The filters 94, 95 are mounted in a chopping wheel 96 whichrevolves about axis X—X to allow energy to pass through differentfilters 94, 95 at different times. The filter 94 will preferably passlight at about 1040 wavenumbers for an absorption of glucose indication.Filter 95 will pass light at 960 wavenumbers to account for shifts intransmission at the glucose absorption number (1040 wavenumber) that arenot attributable to glucose.

The infrared source 92 also generates heat which evaporates off thefluid contained within the capillary tube 12. As a result, theconstituents of the interstitial fluid remain as a residue deposit onthe interior wall of the capillary tube 12. The filtered infraredradiation (which is of a wavelength absorbable by blood glucose or anyother constituent to be measured) passes through the IR transparentcapillary tube 12. Positioned on a side of the capillary tube oppositethe infrared radiation source are two detectors 97, 98. One detector 98directly opposes the infrared radiation passing through the filter wheel96. The other detector 97 opposes and is positioned to receive infraredradiation which is passed through the capillary tube 12. A knife edge 99is provided between the two detectors to prevent the first detector 98from receiving radiation which is passed through the tube 12 and toprevent the second detector 97 from receiving infrared radiationdirectly from the source 92. Preferably, the detectors 97, 98 areslidable on the knife edge 99 so that absorption along the length of thecapillary tube can be measured. The detectors 97, 98 move along thedirection of arrow A in FIG. 4. Alternatively, detectors 97, 98 may befixed and the tube 12 and needle 42 may be axially moved. Finally,detectors 97,98 and tube 12 may remain relatively fixed as long as theresidue deposit in tube 12 is uniform or the entire tube is within thedetectors' field of view.

The detectors 97, 98 are preferably any type of detector that can detectinfrared radiation and provide a signal indicative of the amount ofinfrared radiation detected. The detectors 97, 98 provide the signals toa circuit 100. The circuit 100 compares the received radiation asmeasured by the first detector 98 at a first period in time whenreference filter 95 is in place and the radiation received at a secondperiod of time when test filter 94 is in place and the measurements areratioed. The signal received by the second detector 97 is similarlyratioed by the circuit. The two detectors' ratios are then ratioed byeach other to produce a single number which is proportional to theconcentration of glucose in the interstitial fluid sample. If required,the tube 12 can be measured prior to obtaining the sample in the samemanner described above. This empty tube measurement can be used toaccount for material and geometry variations from tube to tube. It willbe appreciated that the detectors and electronics for providing such ananalysis form no part of this invention per se and may be such as thatshown and described in U.S. Pat. No. 5,115,133.

By way of example, let:

AB₉₇=Energy detected by detector 97 with the absorption filter 94between source 92 and tube 12;

REF₉₇=Energy detected by detector 97 with the reference filter 95between source 92 and tube 12;

AB₉₈=Energy detected by detector 98 with the filter 94 between source 92and detector 98; and

REF₉₈=Energy detected by detector 98 with the filter 95 between source92 and detector 98;

Ratio_(TEST)=(AB₉₇/REF₉₇)_(TEST)/(AB₉₈/REF₉₈)_(TEST)

Where “TEST” indicates measurements taken through a tube 12 contain afluid sample;

Ratio_(START)=(AB₉₇/REF₉₇)_(START)/(AB₉₈/REF₉₈)_(START)

Where “START” indicates measurements taken through an empty tube 12.

With the above definitions, Ratio_(TEST) is inversely proportional tothe glucose concentration in the measured sample. The relation betweenthe ratio_(TEST) and the concentration can be empirically measured andstored in the memory of circuit 100. With the circuit 100 receiving thereadings of detectors 97,98, the ratio is easily calculated and comparedto the memory to determine the concentration and provide a read-outthereof. If material or geometry variations of the tube 12 cannot becontrolled, the ratio of Ratio_(TEST)/Ratio_(START) can, alternatively,be used to compare to the empirical data to determine blood glucoseconcentration.

From the foregoing, the reader will note that a preferred embodiment tothe present invention includes drying of the collected sample by meansof heating the capillary tube 12 with the infrared source 92 in order toevaporate the liquid from the capillary tube 12. The drying measurementprovides numerous advantages. Optical measurement allows quantitativeanalysis of fluid volumes too small to be otherwise chemically analyzed.Also, evaporating the liquid from the tube 12 removes water which is themajor energy absorber in a wet measurement system. As a result, theaccuracy of the measurement is increased because there is no need todistinguish energy absorption of an analyte (for example, glucose) fromIR absorption by water. Also, when performing infrared spectrometry ofanalytes in solution, the path length must be measured accurately or anapparent path length accurately determined.

In the event a dry method is used, it is preferable to first measure theheight which the fluid achieves in the capillary tube 12. Since thecapillary tube 12 diameter is pre-determined (within manufacturingtolerances), the volume of the withdrawn fluid can be measured beforedriving off the fluid with heat from source 92. When the amount ofglucose within tube 12 is determined through the dry technique bypassing the sensors 97, 98 along the length of the tube 12, theconcentration can be calculated since the volume of the fluid has beenpre-measured.

In the event a wet measurement technique is desired (i.e., measuring theglucose level of the fluid without first evaporating the fluid from thetube 12), the apparatus of FIGS. 7–10 is preferably employed.

As discussed previously, a variety of structures may be utilized as thecollection apparatus according to the principles of the presentinvention. Referring now to FIGS. 7–9, an alternative embodiment of thepresent invention is shown. This alternative collection apparatus 10″,similarly includes a hollow needle 42′ and a hollow capillary tube 12′open at both ends and securely disposed within the needle 42′. Theneedle 42′ includes a first flange 100′ disposed against the outer wallof the needle 42′ to control the depth of the penetration of the needle.As shown in FIG. 7, the collection apparatus 10″ is inserted into theskin 20′ until the flange 100′ rests against the surface of the skin20′. In this position, the distal end 14′ of the capillary tube 12′ isdisposed within the upper third portion of the dermal layer 24 of theskin and the capillary action of the tube 12 draws interstitial fluidinto the passageway 18′ of the tube 12′ to collect the sample. It isappreciated that a vacuum mechanism could also be adapted for use withthis collection apparatus to assist the flow of interstitial fluid intothe capillary tube.

The proximal end of the needle 42′ includes a gripping flange 102′ whichprovides a handle for inserting and removing the collection apparatus10″ from the skin 20. Flange 102′ is open at 103′ to vent capillary tube12′. The needle 42′ includes diametrically opposing apertures 46′ forexposing a portion of the capillary tube 12′. After a sample ofinterstitial fluid has been collected within the capillary tube 12′, thecollection apparatus 10″ is removed from the skin 20 and a testing lightsource (preferably transmitted through optical fibers 104′ shown in FIG.8) is then directed through the apertures 46′ to determine theconcentration of a constituent in the interstitial fluid.

In a wet technique, the liquid within the tube 12′ is not evaporated.Instead, infrared radiation having a wavelength absorbable by glucose ispassed through the apertures as illustrated in FIG. 8. If the diameterof the tube 12 is strictly controlled and known, the actual path lengthof the infrared radiation is known. However, if the diameter cannot bestrictly controlled, the path length can be measured throughinterferometry techniques. With knowledge of the actual path length, itis well within the skill of the art to determine the amount of glucosebased on the absorbed infrared radiation and to account for absorptionattributable to liquid within the path length.

FIG. 10 shows a still further embodiment of the invention in anapparatus 10′″. In this embodiment (in which elements in common to FIG.8 are numbered identically with the addition of two apostrophes),apertures 46″ are positioned between flanges 100″, 102″. With thisconstruction, optical fibers 104″ may be installed and spectrometricallytesting fluid within tube 12″ while the apparatus 10′″ is in situ withflange 100″ pressed against a skin layer.

The foregoing description identifies structure and apparatus and methodsof testing which eliminate certain of the disadvantages of the priorart. With respect to prior invasive techniques, the present inventionprovides for collecting a sample of interstitial fluid in the dermallayer 24 of the skin utilizing a needle 42 and capillary tube 12 havinga small diameter to minimize the pain of the needle penetration.Additionally, prior invasive techniques require the presence of a largeconcentration of blood vessels and coincidentally associated nerveendings (i.e., such as a fingertip) which increases the pain of theneedle or lanset penetration. The present invention does not have theserequirements since it is collecting interstitial fluid from the dermallayer 24 of the skin 20 and thus may be used on any area of the skinwith minimal pain to the user. With regard to prior non-invasivetechniques, the minimally invasive optical testing of the presentinvention provides for a more accurate reading of the glucoseconcentration of bodily fluids. A significant advantage is measurementof glucose in interstitial fluid rather than through tissue and wholeblood. The interstitial fluid has the same glucose information, but isin a more easily tested form resulting in a more reliable measurement.Blood contains more interferents to IR glucose testing and possibly inhigher concentrations than interstitial fluid (such interferents includeblood cells, cholesterol and protein).

D. Interstitial Fluid Sampling and Alternate Testing Techniques

The foregoing discussion of the present invention illustrates acollection of interstitial fluid and passing infrared light through avolume of the collected fluid (either before or after drying) in orderto determine blood glucose levels. However, the collection method andapparatus of the present invention can be utilized in a variety ofdifferent embodiments for measurement of blood glucose or other fluidconstituents.

With reference to FIGS. 11–14, an alternative embodiment is shown for aninterstitial fluid sampler 200. The sampler 200 includes a base 202 anda cover 204 connected together at a hinge point 205. Shown best in FIG.11, the cover 204 is a ring having an extension 208. The extension 208cooperates with supports 210 and a pivot pin 212 to define the hingepoint 205.

An interior surface of the cover 204 is provided with a membrane 210covering the interior surface of the cover 204. The base 202 has a flatupper surface 212. In FIGS. 11–14, the cover 204 is shown pivoted to anopen position. The cover 204 may be pivoted about hinge point 205 to aclosed position with the membrane 210 resting against and opposing theupper surface 212 of base 202.

Secured to the base 202 and extending axially therefrom is a needle 214.The needle 214 protrudes beyond the lower surface 206 of the base 202.The needle terminates at the upper surface 212 and flush therewith.Formed in the base 202 and exposed through the lower surface 206 is achamber 218. The chamber surrounds the needle 214.

With the construction thus described, the cover 204 may be placed in aclosed position with the membrane 210 abutting surface 212. Accordingly,the membrane 210 is also opposing the needle 214. The base lower surface206 is urged against a patient's skin such that the needle 214penetrates into the skin. Interstitial fluid is drawn or forced throughthe needle 214 resulting in a spot of the interstitial fluid beingplaced on the membrane 210. In this manner, a sample of interstitialfluid is collected on the membrane 210.

With the membrane 210 containing a sample of interstitial fluid, theinterstitial fluid may now be tested for constituents. The testing ofthe sample of interstitial fluid collected on membrane 210 can be donein any number of ways. For example, the cover 204 may be pivoted to theopen position shown in FIGS. 11–14. The collected interstitial fluidwill appear as a spot on the membrane 210. Infrared light may be passedthrough the spot of interstitial fluid on the membrane 210 withabsorption of the IR wavelengths indicating the amount by which desiredconstituents (for example, glucose) are present. Alternatively, thesample can be electro-chemically tested. Electro-chemical testing ofblood glucose is done with miniature sensors such as those discussed inan article entitled “Towards Continuous Glucose Monitoring: In VivoEvaluation Of A Miniaturized Glucose Sensor Implanted For Several DaysIn Rat Subcutaneous Tissue”, Moatti-Sirat et al., Diabetologia (1992)pages 224–230. Other electrodes for testing blood glucose are discussedin an article entitled “An Overview of Minimally Invasive Technologies”,Ginsberg et al., Clinical Chemistry, Volume 38, No. 9, 1992. As anadditional alternative, collected samples can be colormetrically tested.In colormetric testing, the membrane 210 may be a multilayer of paperand chemicals. As the interstitial fluid passes through the layer, thecolor changes. The changing color indicates relative amounts of glucoseconcentration. An example of such is discussed on page 26 in May 1993issue of Diabetes Forecast. Another alternative is an ATR (attenuatedtotal reflectance) measurement of the collected fluid. In the ATRmethod, the collected fluid is passed over an ATR crystal, which may bepart of the fluid collection device. An IR beam is directed into the ATRcrystal, and the evanescent wave of the beam is preferentially absorbedat specific wave lengths indicating the amount by which desiredconstituents (such as glucose) are present. Other potential techniquesfor analyte measurement include luminescence, immunilogical,radioistopic, and others.

In the embodiment of FIGS. 11–15, the interstitial fluid is collected onthe membrane 210. In a preferred embodiment, the membrane 210 is amicroporous material (e.g., nylon) which will provide even wetting anddrying. The membrane should have a high surface area to promote rapiddrying. An example of such a membrane is a 0.2 micron pore size ofNylaflo. Nylaflo is a registered trademark for a nylon disk made byGelman Science, Inc. of Ann Arbor, Mich. Preferably such materials areIR transparent at the absorption wavelength of the constituent beingmeasured. Other examples of membranes are polyethylene, polyacylonitrile(PAN), poly(styrene-acrylonitrile) (SAN) and polyamides (nylon). Whilethe foregoing are high IR transmissive, less IR transmissive materialsmay be suitable. These include polysulfone, polyethersulfone (PES),cellulosics, poly(vinylidene fluoride) (PVDF), poly(ethyleneterephthalate) (PET) and polycarbonate. The membrane material can beformed in a variety of suitable ways including woven, nonwoven, feltedand as a paper.

The needle 214 is preferably as small as possible to avoid pain to auser. For example, needle 214 will be of a size of about 28 to 32 gauge(i.e., 0.36 millimeters outside diameter to 0.23 millimeters outsidediameter) with a presently anticipated preferred size of about 29 gauge.The preferred gauge is limited by the mechanical integrity ofcommercially available needles. Also, while needle 214 could be sizedand have a length sufficient to extend into the subcutaneous tissue andstill be within the intended scope of the present invention, needle 214will preferably be sized to penetrate into the dermis. As previouslydiscussed, the minimum size of the needle 214 and selection of itslength to penetrate into the dermis are made to minimize the possibilityof contact with nerves or penetration of blood vessels.

The apparatus and method of the present invention is intended to removeinterstitial fluid rather than penetrate a blood vessel and removeblood. While it is anticipated some blood may be in the interstitialfluid, it is the desire of the present invention to minimize or avoidthe presence of blood being collected by the sampler. The presentinvention utilizes the membrane 210 which ensures a uniform thicknessand absorption such that the amount of fluid collection per volume ofthe membrane is constant within the region of the spot on the membrane210 at which the interstitial fluid is deposited. Also, with the presentinvention, the membrane 210, can be easily dried. For example, in mostinstances, due to the small amount of fluid being deposited on themembrane 210, the membrane will dry in ambient conditions. If desired,the membrane 210 may be subjected to any heating or blowing in order tothoroughly dry the membrane 210. Removal of water from the collectedsample enhances the measurement for glucose. For example, in a paperentitled “Quantitative Analysis of Aqueous Solutions by FTIRSpectroscopy of Dry-Extract” by DuPuy et al., SPIE, Volume 1575, 8thInternational Conference on Fourier Transform Spectroscopy (1991), pages501–502, the greater identifiability of the IR signature of a drysucrose extract is shown with reference to an absorption spectrum ofsucrose and water.

The spacing of the needle 214 from the walls of the base 202 by means ofthe cavity 218 is for the purpose of providing the surface 206 to forman annular ring surrounding the needle 214 which forces down on apatient's skin to urge interstitial fluid into the needle 214 aspreviously illustrated and discussed with reference to FIGS. 2 and 6.

FIGS. 16–20 show a still further embodiment of the present invention andillustrate a sampler 200′. Sampler 200′ includes a base 202′ having achamber 218′ through which a needle 214′ passes. The needle 214′ issecured to a plate 215′. The plate 215′ rests within an upper chamber218 a′ of base 202′. The plate 215′ is secured from rotational movementrelative to the base 202′ by means of an alignment pin 217′ passingthrough both the base 202′ and the needle plate 215′.

A membrane 210′ such as the aforementioned Nylaflo (membrane 210) issecured by adhesive or mechanical connection or the like to a membranering 219′. The membrane ring 219′ and membrane 210′ are placed againstthe needle plate with the membrane 210′ opposing the needle 214′.

The membrane ring 219′ has an axial hole 221′ through which aninterstitial fluid spot may be viewed after depositing of the spot onthe membrane 210′ by reason of the interstitial fluid passing throughthe needle 214′. The membrane ring 219′ has a hole 223′ to receive thealignment pin 217′. A main housing 225′ is placed over the body 202′with an O-ring 227′ positioned to space the spacer 202′ from the housing225′. An additional hub 227′ is placed within the housing 225′ such thata vacuum source or the like may be applied to the hub 227′ if desired toassist in the draw of interstitial fluid up the needle 214′. It will beappreciated that the needle 214′ and membrane 210′ as well as thespacing on the needle 214′ from the walls 218′ are done for the purposespreviously described.

With the construction thus described, the bottom surface 206′ of thebase 202′ is placed against the patient's skin, interstitial fluid isdrawn up through the needle 214′ and deposited as a spot on the membrane210′. The membrane ring 219′ with the attached membrane 210′ may beremoved and the spot tested for constituency concentrations aspreviously described.

FIGS. 21–22 show a still further alternative embodiment of the presentinvention by means of a sampler 200″. The sampler 200″ includes a baseportion 202″ having a bottom surface 206″ with an axially positionedchamber 218″. The base 202″ also has a flat upper surface 212″. A needlewith the dimensions and structure previously described extends axiallythrough the base 202″ with the needle protruding below the lower surface206″ and flush with the upper surface 212″. A membrane 210″ of Nylaflois positioned on the upper surface 212″ in overlying relation to theneedle 214″. The sampler 200″ also includes a centrally positionedhandle 215″ to permit a user to grasp the sampler between opposing thumband forefinger to force the surface 206″ against the patient's skinresulting in penetration of the needle 214″. Interstitial fluid ispassed through the needle 214″ and deposited on the membrane 210″.Unlike the membrane 210 of FIGS. 11–14 or the membrane 210′ of FIGS.16–20, the sample on the membrane 210″ may be tested by reflectinginfrared light through the sample and off of surface 212″. In theprevious examples, infrared light is passed through the membrane ratherthan reflected.

Other examples of sampling apparatus according to the present inventioninclude a sheet of metal (e.g., a small lance having the sizing recitedabove with respect to the needles 214,214′,214″ to avoid pain and bloodcollection). A membrane such as the material of membranes 210,210′,210″is deposited on the sheet of metal such that interstitial fluid is drawnonto the membrane through capillary wicking or similar action uponinsertion of the sheet metal into the patient's skin. A still furtherexample includes a penetration member in the form of a split sheet ofmetal having a slit defined between opposing surfaces of the metal. Thesplit sheet has the foregoing recited dimension for pain and bloodavoidance. Upon insertion of the sheet into the skin, interstitial fluidis drawn into the slit. The fluid may be deposited on a membrane for IRtesting.

The split sleeve penetration member is illustrated in two embodiments inFIGS. 26–31. In FIGS. 26–28, a split sleeve 400 is shown in the form offolded metallic member having an angled leading edge 402. Cutouts areprovided in the split sleeve 400 to define a cutout area 404 into whicha membrane such as membrane 210 can be placed to receive collectedfluid. The folded over metal of the split sleeve 400 defines a slot 406which is maintained in spaced relation by reason of protruding rib 408to prevent complete closure of the slot 406. The leading end 402 issized similar to the needles 214 such that the leading end 402 may beinserted into the skin with minimal pain and blood loss and with theadvantages previously described. Interstitial fluid is drawn or urgedthrough the slot 406 and deposited on the membrane (not shown butcontained within area 404) for testing as previously described.

FIGS. 29–31 show an embodiment similar to that of FIGS. 24–25 of asampler 200′″ having a base member 202′″ in the form of a ring and ahandle 215′″. The ring includes a cutout central area 210′″. Connectedto the handle 215′″ and extending through the cutout area 210′″ is asplit sleeve penetration member 214′″ which includes a metallic needleend having spaced-apart metallic portions to define a slot 406′″ intowhich fluid can be passed and deposited on a membrane 210′″. The size ofthe penetration member 214′″ is similar to the sizing of needle 214″ forthe advantages previously discussed.

Through the foregoing detailed description of the present invention, ithas been shown how the objects of the present invention have beenobtained in a preferred manner. However, modifications in equivalence ofthe disclosed concepts, such as those which would readily occur to oneskilled in the art, are intended to be included within the scope of theclaims of the present invention.

1. A method for testing a sample of body fluid, comprising: forming anartificial opening into a patient's skin but not through a dermal layerof said skin with a penetration member, wherein said opening is sized toaccess a constituent-containing, substantially blood-free fluid in theskin; drawing a sample of said blood-free fluid into a first portion ofsaid penetration member that is outside of said dermal layer while asecond portion of said penetration member is within said dermal layer;and testing said sample for said constituent.
 2. A method according toclaim 1 wherein said constituent is glucose.
 3. A method according toclaim 1 wherein said sample is tested by passing light through saidsample and measuring an absorption of predetermined wavelengths.
 4. Amethod according to claim 1 wherein said sample is testedcolorimetrically.
 5. A method according to claim 1 wherein said sampleis tested electro-chemically.
 6. A method according to claim 1 whereinsaid sample is tested by attenuated total reflection.
 7. A methodaccording to claim 1 comprising compressing said skin in a regionsurrounding said opening.
 8. A method for testing a sample of bodyfluid, comprising: inserting a penetration member into a patient's skinbut not through a dermal layer of the skin wherein said penetrationmember is sized to access a constituent-containing, substantiallyblood-free fluid in the skin and wherein a first portion of saidpenetration member is outside of said dermal layer while a secondportion of said penetration member is within said dermal layer; andtesting said accessed fluid for said constituent wherein said fluid isdrawn into the first portion of said penetration member prior to saidtesting.
 9. A method according to claim 8 wherein said constituent isglucose.
 10. A method according to claim 8 wherein said sample is testedcolorimetrically.
 11. A method according to claim 8 wherein said sampleis tested electrochemically.
 12. A method according to claim 8 whereinsaid sample is tested by attenuated total reflection.
 13. A methodaccording to claim 8 wherein said penetration member is a needle.